Sarcopenia, the age-related loss of muscle mass and strength, is a significant contributor to frailty and other declines of aging. Many etiologies have been implicated and there is growing evidence that mitochondria and the mitochondrial genome may play a central role. Recent studies suggest a series of events linking oxidative damage to mitochondrial mutations, mitochondrial dysfunction, fiber atrophy and loss. The studies in the current proposal test the correlations observed in earlier work through the genetic manipulation of mitochondrial mutation rate. Our preliminary data show that the mitochondrial targeting of catalase and exonuclease-deficient polymerase gamma mutant mice are important models of decreased and increased mitochondrial mutation rate, respectively. These models will test the causality of mitochondrial mutations in the aging process and pinpoint areas amenable to intervention. My goal is to become an independent investigator studying basic mechanisms of aging and develop disease-modifying therapies that will benefit my older patients. During the proposed funding period, I will acquire new skills in the areas of mouse genetics, husbandry and colony management, satellite cell isolation and culture, and the measurement of mitochondrial function by flow cytometry. These techniques take full advantage of the resources available at the University of Washington, including the Nathan Shock Center of Excellence in the Biology of Aging and the Transgenic Resource Laboratory, in addition to the internationally-recognized expertise of my mentors and collaborators. Specific Aim 1: Test the hypothesis that systemic decreases in oxidative damage will decrease age-associated mitochondrial genetic and enzymatic abnormalities and ameliorate sarcopenia. Specific Aim 2: Test the hypothesis that systemic increases in mtDNA mutations will increase age- associated mitochondrial genetic and enzymatic abnormalities and worsen sarcopenia. Specific Aim 3: Using a conditional mitochondrial mutator mouse, I will test the susceptibility of skeletal muscle to selective expression of the mtDNA mutator phenotype and establish the relationship between occurrence and biological impact of mtDNA deletion mutations. RELEVANCE: The proposed studies will uncover the basic changes that occur with aging in skeletal muscle which are major contributors to frailty. Elucidating the basic mechanisms of muscle aging will suggest points for therapeutic intervention to prevent this age-related decline. Additionally, this Career Development Award will support the unique career of a physician-scientist working in the areas of gerontology and geriatric medicine, for which there is a growing public health need.